HIV-1 can infect the central nervous system (CNS) causing the AIDS psychomotor complex including the HIV-1-associated leukoencephalopathy and myelopathy We have investigated the role of tumor necrosis factor (TNF) alpha in HIV-1 encephalopathy using purified microglial cultures derived from adult human brain. Such cells are activated and express TNF alpha, just as they do in the brain tissue of patients with AIDS psychomotor complex. When infected with HIV-1 in the continuous presence of TNF alpha antibody, HIV-1 expression and virus growth in microglial cells are strongly inhibited for over a week, suggesting that TNF alpha naturally produced in this in vitro system may enhance HIV-1 replication. Moreover, microglial cell-derived TNF alpha are toxic for oligodendrocytes, the CNS myelin-forming cells and may cause the demyelination observed in the HIV-1 leukoencephalopathy. To investigate this possibility, we have developed an in vitro assay in which TNF alpha induced-cell death of purified rat and-or human oligodendrocytes can be accurately measured. Using this assay, we found that recombinant human TNF alpha as well as TNF-alpha derived from activated human microglia is toxic for 25-30% of rat and human oligodendrocytes in vitro. Moreover such toxicity can be induced by coculturing human microglia with human oligodendrocytes and neutralized in great part by TNF alpha inhibitors such as pentoxifylline (PTX), anti-TNF alpha antibodies and soluble TNF alpha receptors. As PTX is a potent inhibitor of both HIV-1 replication and TNF-alpha synthesis and is presently used in phase 1 trial in AIDS patients, it is possible that this drug may delay the onset of the AIDS psychomotor complex. Our ongoing studies aimed to determine (1) whether TNF-alpha can be cytotoxic for oligodendrocytes in vivo; and (2) the molecular basis of this cytotoxicity.